EGFR/ErbB2-Targeting Lapatinib Therapy for Aggressive Prolactinomas

Abstract

Context: Approximately 10% to 20% of prolactinomas are resistant to dopamine agonist therapy. The ErbB signaling pathway may drive aggressive prolactinoma behavior.

Objective: We evaluated lapatinib, an ErbB1-epidermal growth factor receptor (EGFR)/ErbB2 or human EGFR2 (HER2) tyrosine kinase inhibitor (TKI), in aggressive prolactinomas.

Design: A prospective, phase 2a multicenter trial was conducted.

Setting: This study took place at a tertiary referral pituitary center.

Patients: Study participants included adults with aggressive prolactinomas showing continued tumor growth despite maximally tolerated dopamine agonist therapy.

Intervention: Intervention included oral lapatinib 1250 mg/day for 6 months.

Main outcome measures: The primary end point was 40% reduction in any tumor dimension assessed by magnetic resonance imaging at study end; tumor response was assessed by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included prolactin (PRL) reduction, correlation of response with EGFR/HER2 expression, and safety.

Results: Owing to rigorous inclusion criteria, of 24 planned participants, only 7 consented and 4 were treated. None achieved the primary end point but 3 showed stable disease, including 2 with a 6% increase and 1 with a 16.8% decrease in tumor diameter. PRL response was not always concordant with tumor response, as 2 showed 28% and 59% increases in PRL. The fourth participant had a PRL-secreting carcinoma and withdrew after 3 months of lapatinib because of imaging and PRL progression. EGFR/HER2 expression did not correlate with treatment response. Lapatinib was well tolerated overall, with reversible grade 1 transaminitis in 2 patients, grade 2 rash in 2 patients, and grade 1 asymptomatic bradycardia in 2 patients.

Conclusions: An oral TKI such as lapatinib may be an effective option for a difficult-to-treat patient with an aggressive prolactinoma.

Trial registration: ClinicalTrials.gov NCT00939523.

Keywords: ErbB; HER2; epidermal growth factor receptor; lapatinib; prolactinoma; tyrosine kinase inhibitor.

Figure 1.

Effect of lapatinib therapy on tumor size. Changes in A, tumor diameter, and B, tumor volume based on magnetic resonance imaging (MRI) performed at baseline, 3 months, and 6 months. Patient 1 withdrew after 3 months of treatment.

Figure 2.

Magnetic resonance imaging (MRI) at baseline and study end. A, MRI of patient 1 at (left) baseline and (right) study end. Baseline MRI demonstrates a parasagittal mass on the right side. Lesion measures 17 × 22 × 26 mm. MRI after 3 months of lapatinib therapy shows a 141% increase in tumor diameter now extending to the left. Lesion measures 36.7 × 27 × 41 mm. In addition, there is a new dural metastasis. B, MRI of patient 2 at (left) baseline and (right) study end. Baseline MRI demonstrates a heterogeneous lesion with ill-defined margins and adjacent normal structures. Note extension into the left sphenoid sinus, parasellar structures, anterior clinoid, and superior clivus. The infundibulum is midline to slightly deviated toward the left side. Optic chiasm is normal. Lesion measures 21.8 × 26.8 × 26.1 mm. MRI after 6 months of lapatinib therapy shows a 16.8% decrease in tumor diameter. Lesion measures 16.6 × 22.3 × 24.1 mm. C, MRI of patient 3 at (left) baseline and (right) study end. Baseline MRI demonstrates a large pituitary mass that expands downward, ventrally, superiorly, and posteriorly, including into the interpeduncular cistern and the right temporal fossa, and compressing the right optic nerve. There are areas of hemorrhage within the mass. Lesion measures 48 × 24.4 × 34.6 mm. MRI after 6 months of lapatinib therapy shows a 6% increase in tumor diameter on the right-sided posterior component. Lesion measures 50.9 × 26.6 × 35.1 mm. D, MRI of patient 4 at (left) baseline and (right) study end. Baseline MRI demonstrates a lobulated mass associated with the undersurface of the optic chiasm and extending into the bilateral suprasellar cisterns. Lesion measures 16.3 × 8.6 × 24.5 mm. MRI after 6 months of lapatinib therapy shows a 6.1% increase in tumor diameter in each dimension. Lesion measures 15.8 × 9.2 × 26 mm.

Figure 3.

Effect of lapatinib therapy on prolactin (PRL). Values shown are from baseline and monthly visits. Patient 1 withdrew after 3 months of treatment.